Sunday, November 8, 2015

FCR: The Empire Strikes Back

I'm not really a huge Star Wars guy, but the title seemed appropriate for the content.  For web savvy CLL patients FCR is a lot like the "evil empire."  With two new papers on this regimen, FCR is making a strong push in selected patients.

If a patient was offered a huge likelihood of long term disease control (as in just about every patient would be disease free at 7-8 years post treatment) AND many of those long term remissions were actually looking a lot like cures - would you take FCR?

In today's CLL climate, web informed patients are rebelling against FCR - and in many cases, I think it is for good reason.  FCR is a tough regimen.  Even in the German CLL8 study, about 4% of patients die in the first 12 months after starting therapy.  In the MD Anderson data set, it appears that unusual infections are increased as far out as two years from therapy.  The long term risk of marrow compromise and secondary cancers is real.

But....  In appropriately selected patients, it is probably all worth it.

Two new data sets shed important new data on this regimen that is now almost 15 years old.  An update from the MD Anderson group shows that patients with IgHV mutated CLL have impressive median progression free survival in excess of 12.8 years and that no relapses happened in any patients who made it to 10 years (in other words - if you made it 10 years, you appear to be free and clear). The numbers were comparatively poor however for those patients with IgHV unmutated CLL.  This test should be absolutely CENTRAL to the management of CLL patients being considered for aggressive chemoimmunotherapy - but unfortunately we have data to show that the test is woefully underperformed.

The German group has updated their analysis of the FC vs FCR study with a focus on cytogenetic risk groups with best outcomes.  They validate the role of IgHV status with incredible rates of long term disease control in patients with IgHV mutated CLL particularly those lacking 17P.  For those patients with trisomy 12 not a single patient experienced progression and the del 13Q folks did extremely well too.  I talked with Stilgenbauer recently and he is still reticent to use the word CURE, but I think these subgroups (IgVH mutated WITH either Trisomy 12, or Del 13Q) have high likelihood of super long term disease control if not cure.

None the less, FCR is clearly not for everyone.  If you look at inclusion criteria for FCR studies, only a small number of "typical" CLL patients would be considered eligible.  Furthermore, from the German CLL10 study, we know that the benefit of FCR over BR is primarily in those patients less than age 65.  The median age of frontline treatment in the US is closer to 72.   I will be eager to see subsequent analysis looking at FCR in patients above age 65 who have the favorable marker profile - that remains a question mark for me.

SO... to summarize

For patients with CLL who need therapy, it is imperative to test for FISH and for anyone considering intensive chemoimmunotherapy - IgHV mutation analysis is a must.  For patients less than age 65 with IgHV mutated CLL and either trisomy 12 or del 13Q, should seriously consider FCR as these groups have exceptionally high rates of progression free survival (like about 90% and I believe many of these will prove to be cured).

While FCR has been pushed back in the minds of many following the introduction of novel agents, this small subgroup has results that may help best define the "home" for FCR.

That doesn't answer what to do for those patients with IgHV unmutated CLL, but in my own mind, the long term outcome of FCR in this population (provided there is no 17P deletion) is considerably less favorable and I tend to prefer bendamustine based regimens.  While FCR may still have better "frontline" outcomes than BR in patients less than age 65 according to CLL10, BR is clearly a lot easier to tolerate and I expect lower long term toxicity.  Because our options in relapsed CLL are so darn good, not sure you need the incremental benefit of FCR in the frontline if it really beats up your marrow for the future.

The German "GREEN" study of Bendamustine with obinutuzumab has reported really excellent results with the swapping of rituximab for obinutuzumab and is something we are researching within US Oncology.  Obviously any opportunity to add a novel targeted agent (BTK, PI3K, BCL-2) to this regimen would be great, but currently those combinations have not been approved and are not available outside of a clinical trial.

Anyhow, wanted to get a blog post up.  It has been way too long.  Lots of stuff happening in my own life that has me busier than ever.  Getting an hour here and there for a blog post is a rarity these days. Hopefully this is still valuable.


To leave a comment, click on the title of this post then scroll down to the bottom.  There should be a place to enter comments.





32 comments:

  1. Still very valuable Dr. Sharman, I have been missing your blog posts! This may not be a real strategy until Venetoclax is approved and/or other shorter term novel combo therapies are available... But wouldnt it make sense to begin therapy with novel therapies and exhaust that avenue until MRD- is reached, and if not reached, go to as few cycles as may be needed to get to MRD-? How would you quantify the risk of chemo induced secondary cancers, immune comprised mortality, and AML/MDS for younger patients? Thank you!

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    1. Makes sense, but will need to be tested. Many things in medicine appear to "make sense" until we discover something negative we didn't anticipate. BCL-2 inhibitors appear to be the only novel agent that reliably / quickly achieves MRD negativity

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    2. I guess the reason I chose to participate in the ACP-196 trial frontline instead of doing FCR (I'm mutated, 13q only) was because of the possible long term risks associated with FCR. And since I'm a younger patient of 55, I was concerned that those risks (chemo induced secondary cancers, immune comprised mortality, and AML/MDS) would potentially have a longer time to develop, making them more of a risk to me than an older patient.

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    3. That is a super good drug. Really the difference gets into philosophical differences of approach. It isn't to say that what you are doing is right / wrong, it is that we are unlikely to know the right answer until at least initial results are out for FCR vs Ibrutinib and then they take apart the different subgroups. That may still be a few years away.

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    4. Agreed Anon on ACP trial. I am under 50 yrs also, mutated, 13q del, which would normally fit the ideal FCR profile. It seems w/ FCR there is a ~10% chance of AML/MDS, another ~5% of RT, and an impossible to quantify but much greater than zero chance of chemo-induced secondary cancers or treatment related/immune compromised mortality.

      To Dr. Sharman's point, its my belief that the "health cost-benefit" of ACP196 or ABT199 is not likely worse than the "health cost-benefit" to the more toxic chemo, and sets us up probably better for second line treatment. Especially given my age, I lean more towards the newer agents. But the hard data doesn't really back it up.... yet.

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  2. Just a quick response to your closing comment--yes, Dr. Sharman, your posts are very valuable and appreciated. Thanks for finding the time to do them.

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  3. Would FCR still be a good choice at relapse say 3 years after treatment if still Trisomy 12 and IGHV mutated?

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    1. Very good question for which I don't know the answer. Probably depends to some degree on what you were treated with up front. If after BR, less enthusiastic. If after something less than standard like rituximab monotherapy, would give serious consideration. Would make sure FISH was repeated and even consider looking directly for TP53 gene mutations

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  4. THANKS for this overview! In about an hour, we are chatting with UCSD about treatment for hubby (11q and 13q del, unmutated, age 55, feels good). There is a local BG trial thru RMCC to ponder, but will be interested to hear the non-chemo trials that might be recommended. Keep it coming, Dr. S!

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  5. I might advise caution in the area of unmutated issues. I'm 17p deleted but only 4% of my cells fall into that category. FCR in 2010 still holding. So patients with 17p would do well to find out what percentage of their CLL cells are involved.

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    1. Not all 17P created equal - please see post on that topic. The percentage of positive cells can influence outcome to therapy. Worth rechecking at relapse as "typically" 17P will be the population of cells that comes back, but not always

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  6. Thank you so much for your time wring these blogs which explain so much plainly to so many ..we share these on the Cllsupport fb page often ... And for me as your patient it saves me asking so much when im there.. You don't have to write these blogs, but please know that they are much apoeciated by thousands . . You make a difference !

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  7. Love your blog. 90% is fantastic. Ignoring feasibility, would sequencing the CLL driver genes for this subset of patients help us improve beyond 90%? This image comes to mind.

    http://www.nature.com/nature/journal/v526/n7574/images_article/nature15395-f1.jpg

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    1. Yes- fascinating article - it is on my desk currently. I think we should be testing more for these in general practice although specific treatment guidelines are hard to come by - and many docs will not know what to do with the results. Aegis labs has commercial testing for these

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  8. yes, please keep the blog going.. anxious to hear about the new SYK inhibitor you are presenting on at ASH.

    I may face the question of FCR as an option shortly... 59 years old six years into CLL and feeling good and in good health but ALC and WBC numbers closing in on doubling in six months after 5 years of being mostly flat. HG and platelets showing a trend of decline. Mutated and 13 q at last FISH test- about to update FISH- what to do if no 17 p or T 53 shows up?

    And when to do treatment? Worth waiting as long as possible- per traditional watch and wait theory? Move sooner to reduce disease burden and make it easier for novel therapies? Which option leaves most future avenues with least potential damage? Risk and Reward with incomplete knowledge and your life potentially on the line.. What to do...

    Know that your blogs have and will continue to (I hope!) help me filter through the information so when I speak to my docs I will be better informed.

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  9. Hi Dr. Sharman,
    I see that….FCR for patients with IgVH mutated, Trisomy 12, or Del 13Q have high likelihood of super long term disease control if not cure.”

    Do you have experience or knowledge of IgVH mutated patients having Normal FISH? I collected the below information….

    http://updates.clltopics.org/2710-when-fish-results-can-be-mis-leading
    Chaya Venkat
    October 21st, 2010
    “Normal” FISH result is a pig in a poke. It could be something relatively minor, predictive of a low risk variety of CLL. On the other hand, it could be something as dangerous as damaged (but not deleted) TP53gene. We just don’t know. In this context, it is interesting to note that in the FC versus FCR European study patients with “normal” FISH result did not do very well with FCR. I wonder how many of them were actually TP53 dysfunctional, destined to have poor response to FCR from the get-go.

    Sincerely Tom

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    1. So in the German CLL8 update the "normal" group seemed very weird. I even contacted one of the authors about the normal group for his perspective because it was so unusual. They did not seem to do as well as expected. I really do not know how to interpret that result because it is so unlike our other results in that group

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    2. Thanks for your feedback Dr Sharman, I enjoy your video interviews as you detail your explanations in a way I can follow the discussion (almost fully :)).... I continue to probe this CLL8 result for "normal" group but the fact it surprised you is comforting to me should treatment lead me to FCR. My Mom has CLL but didn't do well with FCR. But she couldn't tell me her FISH specifics (nor her doctor when I asked) so I can't draw conclusions. Best Regards Tom

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  10. Just had Dr Keating this week recommend FCR for me even though I'm unmutated. I'm 13q and 50 years old. He says my other prognostic factors are quite favorable and he believes he can get me a long remission despite my unmutated status. He had me convinced and I do trust him but now seeing this blog post I'm so confused and worried again.

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    1. This is an area where there is a diversity of opinion on what to do in this setting and I think it is a very difficult conversation. I should probably make more clear that the above material is my "opinion." Keating is a towering pillar in this field and we may not agree 100% on everything but unclear that there is an absolute right / wrong.

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  11. Thank you for this. I just finished 6 months of FCR and blood and nodes back to normal. Spleen fine etc. However my bone marrow biopsy shows 20% involvement of CLL. Is this a good, not great, result? Will it come back faster? I do have trisomy 12 an my IgHV is mutated. Thanks.

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    1. We generally think that the "deeper" response, the longer it lasts. This would qualify as a partial response to therapy and in general would predict an earlier relapse although we don't yet know how to correlate FISH results to outcomes once a PR is observed. This is the area where testing for SF3B1, NOTCH1, TP53 can be helpful

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  12. What do you consider a remission after FCR? What result do you hope to find as far as percent of CLL involvment?

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    1. Remission is a sloppy term and it is variably defined by different people. The better terminology is partial response, complete response, MRD +/- etc. Ideally you should not see CLL after FCR.

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  13. As a CLL'er fortunate enough to have Dr. Sharman as my oncologist, I thought it might be useful to make a non-medical and I hope not irrelevant comment. For me, I find that while his blog postings are quite esoteric and way beyond my layman's comprehension of my condition, in real life Dr. Sharman's practical application of all of this medical jargon translates into a confidence that the clinical trial I have been on for more than two years under his guidance really has worked in keeping my CLL under control, and I appreciate all that he is doing.

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  14. It's always a great pleasure to read your posts Doc. What about normal caryotyp?
    thanks

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  15. Very thoughtful post. I fully agree. For the small but significant group of patients that are <65 years old, mutated, no comorbidities, and no bad prognostic factors, FCR is an excellent choice.

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    1. Brian, maybe the reason I have so much trouble finding the time to write long blog posts is that I am lousy with words. Your one sentence said exactly what I was trying to communicate. Thanks for the summary!

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  16. Thank you very much for your blog. I am a 55yo woman with 13q, mutated IVgH CLL, diagnosed 3 years ago. My blood numbers are holding steady and I am quite a ways off from requiring treatment. I enjoy your blog as a way to keep myself informed about treatment decisions I will have to make someday. This recent blog was pretty relevant to my case. Thank you for taking the time and energy to reach out and keep us informed.

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  17. Dr Sharman, thank you for your blog and please, if tou can, continue to keep CLL / SLL patients internationally abreast of key developments.
    I am heading to a leading CLL specialist in the UK next week, as my local haematologist is recommending FCR. I am a normal FISH person (whatever that means) and my IgVH test results are pending. However, I was hoping for longer in W and W - just 1.5 years! Bulky lymph nodes are my specific difficulty.
    Your post has given me some peace of mind if my UK specialist confirms that I do indeed need to leave W and W now, and that FCR is my best option.

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  18. Dr Sharman - greatly appreciate all your posts and insights. Would FCR be off the table for someone young, fit (42) with an unmutated IGVH and no 17p in your view?

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